Activation of Notch3 in Renal Tubular Cells Leads to Progressive Cystic Kidney Disease

Background: Polycystic kidney disease (PKD) is a genetic disorder affecting millions of people worldwide that is characterized by fluid-filled cysts and leads to end-stage renal disease (ESRD). The hallmarks of PKD are proliferation and dedifferentiation of tubular epithelial cells, cellular processes known to be regulated by Notch signaling. Methods: We found increased Notch3 expression in human PKD and renal cell carcinoma biopsies. To obtain insight into the underlying mechanisms and the functional consequences of this abnormal expression, we developed a transgenic mouse model with conditional overexpression of the intracellular Notch3 (ICN3) domain specifically in renal tubules. We evaluated the alterations in renal function (creatininemia, BUN) and structure (cysts, fibrosis, inflammation) and measured the expression of several genes involved in Notch signaling and the mechanisms of inflammation, proliferation, dedifferentiation, fibrosis, injury, apoptosis and regeneration. Results: After one month of ICN3 overexpression, kidneys were larger with tubules grossly enlarged in diameter, with cell hypertrophy and hyperplasia, exclusively in the outer stripe of the outer medulla. After three months, mice developed numerous cysts in proximal and distal tubules. The cysts had variable sizes and were lined with a single- or multilayered, flattened, cuboid or columnar epithelium. This resulted in epithelial hyperplasia, which was observed as protrusions into the cystic lumen in some of the renal cysts. The pre-cystic and cystic epithelium showed increased expression of cytoskeletal filaments and markers of epithelial injury and dedifferentiation. Additionally, the epithelium showed increased proliferation with an aberrant orientation of the mitotic spindle. These phenotypic tubular alterations led to progressive interstitial inflammation and fibrosis. Conclusions: In summary, Notch3 signaling promoted tubular cell proliferation, the alignment of cell division, dedifferentiation and hyperplasia, leading to cystic kidney diseases and pre-neoplastic lesions.

Main causes of cattle slaughter condemnation under the state sanitary inspection in Bahia, Brazil

Slaughter condemnations are important sources of information on cattle health and handling. The aim of this study was to evaluate the main causes of condemnation of cattle slaughter under the state sanitary inspection by the Diretoria de Inspeção de Produtos de Origem Agropecuária (DIPA) of Agência de Defesa Agropecuária da Bahia (ADAB), in Bahia, Brazil. A retrospective data of all cattle slaughtered from 2012 to 2019 was obtained from DIPA – ADAB. During this period, 4,635,615 cattle were slaughtered and 1,452,472 (31.33%) condemnations were registered to have occurred at varying levels in all regions of the state. The more condemned organs were kidneys and lungs; and the main causes of condemnation were nephritis (11.79%), congestion (11.20%), emphysema (10.72%), blood aspiration (8.36%), renal cysts (5.75%), and abscesses (5.71%). However, other condemnation causes such as cysticercosis, fasciolosis, and tuberculosis were observed at lower rates. Results showed that the main causes of condemnation of cattle slaughter were not related to zoonotic diseases instead were more involved in partial condemnation of organs.

Generation of heterozygous PKD1 mutant pigs exhibiting early-onset renal cyst formation

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease, manifesting as the progressive development of fluid-filled renal cysts. In approximately half of all patients with ADPKD, end-stage renal disease results in decreased renal function. In this study, we used CRISPR-Cas9 and somatic cell cloning to produce pigs with the unique mutation c.152_153insG (PKD1insG/+). Pathological analysis of founder cloned animals and progeny revealed that PKD1insG/+ pigs developed many pathological conditions similar to those of patients with heterozygous mutations in PKD1. Pathological similarities included the formation of macroscopic renal cysts at the neonatal stage, number and cystogenic dynamics of the renal cysts formed, interstitial fibrosis of the renal tissue, and presence of a premature asymptomatic stage. Our findings demonstrate that PKD1insG/+ pigs recapitulate the characteristic symptoms of ADPKD.

Development of renal adenocarcinoma in a ferret with renal cortical cysts (Mustela putorius furo)

CASE DESCRIPTION A 5.5-year-old 0.929-kg spayed female domestic ferret (Mustela putorius furo) underwent serial abdominal ultrasonographic and clinicopathologic examinations after multiple renal cysts were detected bilaterally during a routine examination. CLINICAL FINDINGS The ferret was apparently healthy at the start of the monitoring period and had no clinical signs for > 20 months. Four months after the initial examination, the largest cyst became increasingly mineralized; 17 months after detection, it had increased in size and become amorphous, and the ferret’s plasma BUN concentration was mildly high. Within 21 months after the first visit, a nodule was detectable, and hydronephrosis developed in the kidney with the largest cyst. Findings for fine-needle aspirates from the nodule were consistent with renal carcinoma. TREATMENT AND OUTCOME Contrast-enhanced CT revealed severe unilateral nephromegaly with no contrast uptake in the affected ureter. Following surgical removal of the affected kidney, histologic examination identified renal adenocarcinoma replacing the entire renal cortex and medulla. The ferret was euthanized postoperatively because of declining condition. On necropsy, metastasis to a mesenteric lymph node was identified; comorbidities included 2 other neoplasms and acute, severe injury of the contralateral kidney. CLINICAL RELEVANCE Neoplastic transformation of a renal cyst was suspected in the ferret of this report on the basis of observed ultrasonographic changes over time and extensive infiltration of the neoplasm throughout the affected kidney. Renal cysts are linked to renal neoplasia in other species, and the findings for this patient supported the need for periodic monitoring of renal cysts in ferrets.

435 Renal denervation in a patient with uncontrolled arterial hypertension secondary to polycystic kidney disease

Aims Autosomal dominant polycystic kidney disease (ADPKD) represents the most common inherited cause of chronic kidney disease. Typical manifestations of this condition include secondary hypertension, abdominal pain, haematuria and urinary tract infections. Despite the progressive increase in the use of antihypertensive therapy in patients with ADPKD in the last decades, reaching blood pressure target is often difficult in this setting due to the complex physiopathology of arterial hypertension in ADPKD. Catheter-based renal sympathetic denervation (RDN) represents nowadays a therapeutic strategy to approach resistant hypertension. Based on consistent results of several sham-controlled clinical trials, the evidence of safety and efficacy of this procedure is increasing, also in patients with multiple comorbidities including chronic kidney disease. Patients with ADPKD often develop chronic severe kidney-related pain, caused by distension of the renal capsule due to the expansion of the cysts. RDN was proposed to be an effective therapeutic option able to relieve loin pain. Methods A 49-year-old man affected by ADPKD was referred to our centre for resistant uncontrolled arterial hypertension, despite combined therapy with five antihypertensive drugs. He also complained about intense loin pain and 3 years earlier underwent two surgical interventions to remove voluminous renal cysts, that did not relieve chronic pain. His kidney function was moderately decreased at presentation, with progressive decline in the previous years. After a multi-disciplinary discussion with a nephrologist and algologist, the patient was proposed for RDN with the aim of lowering blood pressure and reducing pain. He was treated in July 2018, and after the procedure, was observed a better control of blood pressure but no benefits on pain. Because of the persistence of intractable loin pain, the patient was submitted to a second RDN in December 2018. Also, after this procedure, blood pressure declined remarkably, decreasing his need for antihypertensive medications without a significant worsening of kidney function. Unfortunately, no benefit on chronic pain was observed. Results ADPKD is characterized by the progressive bilateral development of focal renal cysts. Cardiovascular complications, mainly related to hypertension, are a major cause of morbidity and mortality for these patients. RDN could be a valid and safe therapeutic option for the treatment of secondary hypertension in this setting.

Prevalence, risk factors and clinical characteristics of renal dysfunction in Chinese outpatients with growth simple renal cysts

Background Researchers have proved that simple renal cysts (SRCs) might be correlated with renal dysfunction, but it is still controversial. Thus, we conducted clinical research study with large sample size and long-term follow-up to clarify the relationship between SRCs and renal dysfunction. Methods A total of 571 SRCs patients in outpatients of nephrology department were included, we investigated the clinical characteristics of growth SRCs compared with non-growth SRCs, evaluated the incidence of renal dysfunction in SRCs and explored the risk factors of renal dysfunction in growth SRCs. Results The mean baseline age was 51.31 ± 14.37 years in the whole cohort, ranging from 19 to 79 years, and 57.6% of them were male. The median follow-up duration was 3 years, ranging from 1 to 10 years. In addition, the final maximum diameter increased 1 mm (2.74%) per year. Patients in growth SRCs group tented to have higher percentage of hypertension, hematuria, large cyst and multiple cysts compared with non-growth SRCs group. The prevalence of renal dysfunction was 15.6% after the follow-up, and the prevalence of renal dysfunction was about 10 times higher in growth SRCs group than non-growth SRCs group (23.3% vs. 2.4%). Renal dysfunction was significantly associated with age, female, total cholesterol, diastolic blood pressure, final maximum diameter and yearly change in maximum diameter in growth SRCs. Conclusions SRCs were closely related to the decline of renal function, we recommend close follow-up for growth SRCs.

Practice Patterns for the Acceptance of Medically Complex Living Kidney Donors with Hematuria, Sickle Cell Trait, Smoking, Illegal Drug Use, or Urological Issues: A Multinational Survey

Background To review the practice patterns for the acceptance of medically complex living kidney donors (MCLKD) among the transplant providers of the international transplant community. Methods We distributed a survey globally, through major international transplantation societies, among nephrologists and transplant surgeons (TS). The survey contained questions regarding potential donors with microscopic hematuria, sickle cell trait, renal cysts, kidney stones, smoking, or illegal drug use. Results There were 239 respondents from 29 countries, including nephrologists (42%) and TS (58%). Although most respondents would investigate microscopic hematuria, one-third of them indicated they would decline these potential donors without investigation. Interestingly, most respondents accepted heavy smokers, intermittent illegal drug users (with advice to quit), and those with incidentally identified kidney stones, remote history of renal colic or simple renal cysts. We found multiple areas of consensus in practice with some interesting differences between nephrologists and TS. Conclusions This survey highlights the practice patterns of the acceptance of MCLKDs among the international community. In the absence of clear guidelines, this survey provides additional information to counsel kidney donors with microscopic hematuria, sickle cell trait, renal cysts, kidney stones, heavy smoking, or illegal drug use.